title: RNA interference targeting raptor inhibits proliferation of gastric cancer cells.
abstract: Mammalian target of rapamycin complex 1 (mTORC1) is dysregulated in gastric cancer. The biologic function of mTORC1 in gastric carcinogenesis is unclear. Here, we demonstrate that disruption of mTORC1 function by RNA interference-mediated downregulation of raptor substantially inhibited gastric cancer cell proliferation through induction of G(0)/G(1)-phase cell cycle arrest. The anti-proliferative effect was accompanied by concomitant downregulation of activator protein-1 and upregulation of Smad2/3 transcriptional activities. In addition, the expression of cyclin D(3) and p21(Waf1), which stabilizes cyclin D/cdk4 complex for G(1)-S transition, was reduced by raptor knockdown. In conclusion, disruption of mTORC1 inhibits gastric cancer cell proliferation through multiple pathways. This discovery may have an implication in the application of mTORC1-directed therapy for the treatment of gastric cancer.
authors.affiliation: Institute of Digestive Diseases, LKS Institute of Health Sciences and Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Shatin, NT, Hong Kong, PR China.
authors.forename: William Ka Kei
authors.initials: WK
authors.lastname: Wu
authors.forename: Chung Wa
authors.initials: CW
authors.lastname: Lee
authors.forename: Chi Hin
authors.initials: CH
authors.lastname: Cho
authors.forename: Francis Ka Leung
authors.initials: FK
authors.lastname: Chan
authors.forename: Jun
authors.initials: J
authors.lastname: Yu
authors.forename: Joseph Jao Yiu
authors.initials: JJ
authors.lastname: Sung
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D000230:Adenocarcinoma / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D015153:Blotting, Western; D018797:Cell Cycle Proteins / Q000378:metabolism; D049109:Cell Proliferation; D016193:G1 Phase; D006801:Humans; D008156:Luciferases / Q000378:metabolism; D000076222:Mechanistic Target of Rapamycin Complex 1; D046912:Multiprotein Complexes; D011506:Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics*; D000076223:Regulatory-Associated Protein of mTOR; D016192:Resting Phase, Cell Cycle; D013274:Stomach Neoplasms / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D058570:TOR Serine-Threonine Kinases; D014407:Tumor Cells, Cultured
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D018797:Cell Cycle Proteins; D046912:Multiprotein Complexes; D011506:Proteins; D034741:RNA, Small Interfering; C463659:RPTOR protein, human; D000076223:Regulatory-Associated Protein of mTOR; D008156:Luciferases; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases